Primary musculoskeletal lymphoma often requires multiple biopsies for tissue confirmation. This challenge is understood by specialists but has not been specifically quantified. One-hundred-eighteen biopsies performed in 100 cases of primary musculoskeletal lymphoma was performed. Demographics, tumor location and the method and performer of biopsy were recorded. Pearson chi-square and analysis of variance (ANOVA) statistics were used to compare rates of diagnostic yield, time to diagnosis and the presence of crush artifact based on method of biopsy, imaging, performer and tumor location. Diagnostic yield of initial biopsy is 82%. Open biopsy is associated with a higher yield compared to percutaneous techniques (p = 0.005). Biopsies performed by the treating surgeon had a higher yield compared to other practitioners (p = 0.035). Musculoskeletal lymphomas are a greater diagnostic challenge compared to other lesions. A higher index of suspicion and more aggressive sampling procedure may be necessary to establish this diagnosis. (Journal of Surgical Orthopaedic Advances 29(3):149-153, 2020).

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